Deriving 3D-QSARs

The MIF-based QSAR models fit well with the known peptide specificities of the WW domains, and aid identification of the important determinants of binding specificity. 

Positive PLS coefficient large side-chain at residue 35 favors binding 

Negative PLS coefficient in region accomodating peptide tyrosine small side-chain at residue 30 favors binding 

Negative PLS coefficient space between Y28 and W39 is necessary for the ligand prolines to stack well with these residues for binding 

Proline-rich peptide with tyrosine at position 3 

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Since the first publication of the method, much experience has been gained and the method has been extended and improved. This chapter discusses for the first time the details of the method, the problems more commonly found in its practical applications and the approach for the interpretation of GRIND-derived 3D QSAR models. 

MIFs can be applied in many ways, and the reader is referred to Cruciani s recently published book on this topic." In addition to their frequent usage in deriving 3D QSARs for low-molecular weight compounds, they can guide the process of structure-based ligand design, they can... 

Since 1988, a few hundred publications, several reviews (e.g.. Refs. 13-18), and three books have appeared on this subject. Despite some major problems in its proper application (cf. Section 7), the method is now generally estimated as a useful tool for deriving 3D QSAR models. 

Imidazolinyl) derivative of 8-methyl-2,3,6,7-tetrahydro-5 f- and 8-methyl-7-methoxy-5-oxo-2,3-dihydro-5 f-pyrido[l, 2, i-de]-1,4-benzoxazines were included in a 3D-QSAR CoMFA study on imidazolinergic I2 ligands (00JMC1109). 

Figure 5.1 Superimposition of the pharmacophoric schemes derived from the 3D QSAR models published by Ekins et al. [14] (vertical lines filling), Cavalli etal. [15] (horizontal lines filling) and Pearlstein etal. [17] (dotfilling). The central black circle represents the...

Figure 3.6 Docking simulations. (Source Liu H, Huang X, Shen J, et al. Inhibitory mode of 1,5-diarylpyrazole derivatives against cyclooxygenase-2 and cyclooxygenase-1 molecular docking and 3D QSAR analyses, Journal of Medicinal Chemistry 45 4816-4827 (2002). Used with permission.)...

Balls, T., Andersen, K., Soby, K.K., and Liljefors, T. al Adrenoceptor subtype selectivity 3D-QSAR models for a new class of al adrenoceptor antagonists derived from the novel antipsychotic sertindole./. Mol. Graph. Mod. 2003, 21, 523-534. 

Moron, J.A., Campillo, M., Perez, V., Unzeta, M., Pardo, L. Molecular determinants of MAO selectivity in a series of indolylmethylamine derivatives biological activities, 3D-QSAR/CoMFA analysis, and computational simulation of ligand recognition./. Med. Chem. 2000, 43, 1684-1691. 

The major hurdle to overcome in the development of 3D-QSAR models using steric, electrostatic, or lipophilic fields is related to both conformation selection and subsequent suitable overlay (alignment) of compounds. Therefore, it is of some interest to provide a conformation-ally sensitive lipophilicity descriptor that is alignment-independent. In this chapter we describe the derivation and parametrization of a new descriptor called 3D-LogP and demonstrate both its conformational sensitivity and its effectiveness in QSAR analysis. The 3D-LogP descriptor provides such a representation in the form of a rapidly computable description of the local lipophilicity at points on a user-defined molecular surface. 

MS-WHIM, new 3D theoretical descriptors derived from molecular surface properties a comparative 3D QSAR study in a series of steroids../. Comput. 

Wright AD, de Nys R, Angerhofer CK, Pezzuto JM, Gurrath M (2006) Biological Activities and 3D QSAR Studies of a Series of Delisea pulchra (cf. fimbriata) Derived Natural Products. J Nat Prod 69 1180... 

The pseudoreceptor modeling concept was utilized for (i) reconstruction of experimentally determined receptor sites, (ii) exploration of crucial ligand-receptor interaction sites and (iii) prediction of pharmacological activities of molecules, sometimes compared with results derived from other 3D-QSAR techniques. 

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